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US3962449A - Cardioactive bispidones and bispidines - Google Patents

Cardioactive bispidones and bispidines Download PDF

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Publication number
US3962449A
US3962449A US05/585,606 US58560675A US3962449A US 3962449 A US3962449 A US 3962449A US 58560675 A US58560675 A US 58560675A US 3962449 A US3962449 A US 3962449A
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US
United States
Prior art keywords
compound
bispidine
methyl
bispidone
phenylethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US05/585,606
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English (en)
Inventor
Fritz Binnig
Manfred Raschack
Hans-Joerg Treiber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott GmbH and Co KG
Original Assignee
Knoll GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Knoll GmbH filed Critical Knoll GmbH
Application granted granted Critical
Publication of US3962449A publication Critical patent/US3962449A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • the present invention relates to compounds of the formula ##SPC3##
  • R' represents lower alkyl, suitably containing 1 to 4 carbon atoms and optionally substituted by a phenyl group
  • R" represents lower alkyl, suitably containing from 1 to 6 carbon atoms and optionally substituted by one or two phenyl groups, with the proviso that R' and R" together contain at least six carbon atoms, to pharmacologically acceptable salts of such compounds, and to pharmaceutical compositions containing at least one of these compounds.
  • the compounds are prepared by subjecting a compound of the formula ##SPC4##
  • anti-arrhythmic preparations such as Antazolin, Lidocain and N-propylajmalin must be used with great care in view of their narrow therapeutic range, that is to say there is only a relatively small difference between the doses which produce an anti-arrhythmic effect and the doses which produce a negative inotropic effect.
  • the anti-arrhythmic effect of the new compounds was shown by determining the functional refractory period of the left auricle of the heart of guinea pigs.
  • the experimental procedure utilized paired electrical stimulation in an adaptation of the method of W. C. Govier, J. Pharmacol. Exp. Therap. 148, 100- 105 (1965).
  • the numerous known anti-arrhythmical preparations of differing structure and point of therapeutic attack all show an prolongation of the functional refractory period.
  • the experiment additionally permits a study of the effects of different substances on the contractility of the heart muscles [Reuter und Heeg, Naunyn, Naunyn-Schmiedeberg's Arch. Pharmakol.
  • Table 1 the effects of two typical representatives of the compounds according to the present invention are compared with those of known anti-arrhythmically effective compounds.
  • column II the anti-arrhythmic effect is shown and in column III, the inotropic effect is shown.
  • column IV the therapeutic range of the compounds is shown.
  • the ED 25 is the effective dose which extends the refractory period by 25% or lowers the contractional force by 25%, respectively.
  • the Table shows that the substances in accordance with the present invention are clearly superior to the known substances both with regard to safety margin between the desired rhythm regulating effect and the undesired impairing of the contractional forces of the heart.
  • the anti-arrhythmic potency of bispidine derivatives could also be shown by their effect on experimentally induced heart rhythm disturbances in intact experimental animals. If rats are continuously infused intravenously with aconitine, then serious disturbances of the cardiac rhythm such as extrasystole, ventricular tachycardia, and ventricular flutter, which finally lead to the death of the experimental animals, can be observed on an electrocardiogram. By pre-treatment with, for example, N-isopropyl N'- ⁇ -phenylethyl-bispidine or N,N'-dibenzyl bispidine, the occurrence of these heart rhythm disturbances is prevented or at least substantially delayed even if aconitine is continuously injected.
  • This experimental arrhythmic model is checked by means of clinically tested standard therapeutic compounds as to its reliability and is well suited for characterizing antiarrhythmical compounds in experiments on animals [cf. for example, Bianci et al., Arzneim.-Forsch. 18, 845- 850 (1968); Haas und Busch, Arzneim.-Forsch. 18, 401- 407 (1968); Haas et al., Arzneim.-Forsch. 21, 1392- 1399 (1971); Marmo, Naunyn-Schmiedeberg's Arch. Pharmakol. 269, 231- 247 (1971); and Strubelt et al., Naunyn-Schmiedeberg's Arch. Pharmakol. 271, 346- 360 (1971.]
  • the ED 25 or ED 50 are the intravenous dosages in mg/kg which allow an increase in administered aconitine doses, relative to the control, by 25 or 50%, respectively, before the occurrence of extrasystoles, ventricular tachycardia, and ventricular flutter.
  • This Table also shows the superior effect of the substances in accordance with the present invention when administered intravenously.
  • the anti-arrhythmic compounds according to the present invention are about 10 times more effective than procainamide when administered orally.
  • they have no blood pressure lowering effect.
  • the new compounds may be administered orally, intravenously, and intramuscularly.
  • the effective dose lies within the range of 1 to 10 mg/kg per day when given orally and within the range of 0.05 to 1.0 mg/kg per day when administered intravenously or intramuscularly.
  • the compounds may be administered in any suitable form, such as, for example, tablets, coated tablets, lozenges, and solutions.
  • the synthesis of the claimed bispidones by a Mannich reaction is suitably performed, in a manner known in the art, in an inert organic solvent in the presence of an organic or inorganic acid.
  • Tetrahydrofuran, chloroform, methylene chloride and, particularly, methanol, ethanol, and isopropanol are suitable solvents for the reaction medium.
  • Glacial acetic acid and hydrochloric acid are the acids which are preferably utilized in the reaction.
  • the formaldehyde may, if desired, be in the form of paraformaldehyde. It is advantageous if the reaction is effected at an elevated temperature, such as the boiling point of the solvent or solvents being employed.
  • the benzyl group may be removed by known techniques for catalytic hydrogenation.
  • the amine thus obtained may be alkylated or aralkylated, as known in the art, with a halogen compound of the formula R' -Hal or R" -Hal, wherein R' and R" are as aforementioned and Hal represents a halogen atom, preferably a chlorine atom.
  • the reaction with the halo-compound is preferably carried out in the presence of an alkali metal carbonate in an inert solvent having a relatively high boiling point, such as xylene or methyl isobutyl ketone.
  • Bispidines are prepared by reduction of the corresponding bispidones by techniques known in the art, for example using hydrazine hydrate in basic solution.
  • the bispidones and bispidines can be salified with a physiologically compatible acid, as known in the art.
  • physiologically compatible salts include those obtained from hydrochloric acid, sulfuric acid, phosphoric acid, fumaric acid, maleic acid, succinic acid, tartaric acid, or citric acid, among other suitable acids known in the art.
  • Paraformaldehyde (63 g) was suspended in a mixture of methanol (1000 ml), benzylamine (107 g), and glacial acetic acid (62 g) in a three-necked flask having a capacity of four liters. This mixture was boiled under reflux and, over a period of 30 minutes, a solution of N-benzylpiperidone-4 (189 g) and glacial acetic acid (60 g) in methanol (700 ml) was added dropwise, with stirring. After a further three hours, the solvent was completely removed by distillation.
  • N,N'-dibenzylbispidone 95 g
  • potassium hydroxide 98 g
  • triethyleneglycol 650 ml
  • hydrazine hydrate 65 g; 80 %
  • the volatile components were distilled off, until the internal temperature had risen to 220°C.
  • both the distillate and the residue were diluted with 600 ml water, and were thoroughly extracted with ether.
  • vacuum distillation was effected.
  • analytically pure N,N'-dibenzylbispidine 68.5 g, 75.5% of the theoretical yield
  • the hydrochloride melts at 84° to 86°C, when recrystallized from isopropanol.
  • N-methylbispidine 14 g, 0.1 mol
  • N-methylbispidine 14 g, 0.1 mol
  • 24.7 g (0.1 mol) benzhydryl bromide 24.7 g, 0.1 mol
  • potassium carbonate 13.8 g, 0.1 mol
  • the reaction product was cooled and mixed with water, the organic phase being separated and evaporated. The residue was distilled in a high vacuum. The oil solidified on standing and was recrystallized from di-isopropylether.
  • N-methylbispidine 14 g, 0.1 mol was boiled under reflux with stirring for 5 hours with 4,4-diphenyl butyl chloride (24.5 g, 0.1 mol) and potassium carbonate (13.8 g, 0.1 mol) in xylene (250 ml).
  • the reaction product was cooled and mixed with water.
  • the organic phase was separated and dried with anhydrous sodium sulfate, the solvent distilled off, and the residue distilled in vacuo.
  • N-isopropyl N'- ⁇ -phenylethyl bispidine (10 g) was dissolved in water (5000 ml), with the addition of NaCl and an equimolecular quantity of acetic acid, so as to form a blood isotonic solution.
  • the solution was filled into 5 ml ampules and sterilized.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US05/585,606 1974-06-14 1975-06-10 Cardioactive bispidones and bispidines Expired - Lifetime US3962449A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2428792A DE2428792A1 (de) 1974-06-14 1974-06-14 Neue antiarrhythmika
DT2428792 1974-06-14

Publications (1)

Publication Number Publication Date
US3962449A true US3962449A (en) 1976-06-08

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US05/585,606 Expired - Lifetime US3962449A (en) 1974-06-14 1975-06-10 Cardioactive bispidones and bispidines

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US (1) US3962449A (xx)
JP (1) JPS5111791A (xx)
AT (1) AT343660B (xx)
BE (1) BE830153A (xx)
CA (1) CA1058181A (xx)
CH (1) CH618168A5 (xx)
DE (1) DE2428792A1 (xx)
FI (1) FI57759C (xx)
FR (1) FR2274300A1 (xx)
GB (1) GB1445967A (xx)
NL (1) NL7506886A (xx)
SE (1) SE420727B (xx)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4183935A (en) * 1977-06-13 1980-01-15 Basf Aktiengesellschaft Bispidine derivatives, their preparation, and drugs containing same
US4550112A (en) * 1982-09-18 1985-10-29 Kali-Chemie Pharma Gmbh 3,7-Diazabicyclo(3,3,1)nonane compounds and their use in treating heart disease
US4906640A (en) * 1987-07-04 1990-03-06 Kali-Chemie Pharma Gmbh 3-sulfonyl-3,7-diazabicyclo[3,3,1]nonane compounds and medicaments containing said compounds
US4912113A (en) * 1987-09-09 1990-03-27 Kali-Chemie Pharma Gmbh 3,7-diazabicyclo(3,3,1)nonane compounds and pharmaceutical compositions containing such compounds
US5164401A (en) * 1990-06-15 1992-11-17 Kali-Chemie Pharma Gmbh Method of diuretic treatment with 3,7-diazabicyclo[3,3,1]nonane compounds
US6291475B1 (en) 1997-12-17 2001-09-18 Astrazeneca Ab Bispidine antiarrhythmic compounds
US6559162B2 (en) 1999-12-23 2003-05-06 Astrazeneca Ab Azabicyclooctane derivatives useful in the treatment of cardiac arrhythmias
US20030212095A1 (en) * 2000-07-07 2003-11-13 Kjell Andersson New bispidine compounds and their use in the treatment of cardiac arrhythmias
US20040023971A1 (en) * 2000-10-20 2004-02-05 Magnus Bjorsne 3,8-Diazabicyclo[3.2.1]octanes and their use in the treatment of cardiac arrhythmias
US20040039199A1 (en) * 2000-10-02 2004-02-26 Magnus Bjorsne Oxabispidine compound useful in the treatment of cardiac arrhythmias
US20040053986A1 (en) * 2001-02-02 2004-03-18 Magnus Bjorsne 3,7-Diazabicyclo[3.3.0]octanes and their use in the treatment of cardiac arrhythmias
US6808924B1 (en) 2000-07-11 2004-10-26 Claudia Lanari Mouse mammary tumor lines expressing estrogen and progesterone receptors
US20040229900A1 (en) * 1999-06-16 2004-11-18 Astrazeneca Ab Bispidine compounds useful in the treatment of cardiac arrythmias
US20050004113A1 (en) * 1999-06-16 2005-01-06 Astrazeneca Ab New bispidine compounds useful in the treatment of cardiac arrhythmias
US6887881B1 (en) 1999-06-16 2005-05-03 Astrazeneca Ab Bispidine compounds useful in the treatment of cardiac arrythmias
WO2005123748A1 (en) 2004-06-15 2005-12-29 Astrazeneca Ab Novel oxabispidine compounds and their use in the treatment of cardiac arrhythmias
US7038054B1 (en) * 1999-09-03 2006-05-02 Pharmacopeia Drug Discovery, Inc. Diazabicyclononane scaffold for combinatorial synthesis
US20070259864A1 (en) * 2004-06-15 2007-11-08 Astrazeneca Ab Novel Oxabispidine Compounds and Their Use in the Treatment of Cardiac Arrhythmias
US20090054422A1 (en) * 2005-06-13 2009-02-26 Astrazeneca Ab New Oxabispidine Compounds For The Treatment Of Cardiac Arrhythmias

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3112055A1 (de) * 1981-03-27 1982-10-07 Basf Ag, 6700 Ludwigshafen Bispidinderivate, ihre herstellung und diese enthaltende arzneimittel
HU184960B (en) * 1981-07-20 1984-11-28 Richter Gedeon Vegyeszet Process for preparing new derivatives of 3,7-diazabicyclo/3.3.1/ nonane
DE3730224A1 (de) * 1987-09-09 1989-03-23 Kali Chemie Pharma Gmbh 3-cinnamyl-3,7-diazabicyclo(3,3,1) nonan-verbindungen sowie verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
DE4324086A1 (de) * 1993-07-17 1995-01-19 Basf Ag Verfahren zur Herstellung von N,N`-Dibenzylbispidin
SE0302775D0 (sv) * 2003-10-20 2003-10-20 Astrazeneca Ab Chemical compound and assay

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3167561A (en) * 1963-02-05 1965-01-26 Merck & Co Inc 2, 5-diazabicyclo-[2,2,1]heptanes and [2,2,2]octanes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3167561A (en) * 1963-02-05 1965-01-26 Merck & Co Inc 2, 5-diazabicyclo-[2,2,1]heptanes and [2,2,2]octanes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Douglas et al., J. Org. Chem. 33 (1), 355-359 (1968). *

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4183935A (en) * 1977-06-13 1980-01-15 Basf Aktiengesellschaft Bispidine derivatives, their preparation, and drugs containing same
US4550112A (en) * 1982-09-18 1985-10-29 Kali-Chemie Pharma Gmbh 3,7-Diazabicyclo(3,3,1)nonane compounds and their use in treating heart disease
US4906640A (en) * 1987-07-04 1990-03-06 Kali-Chemie Pharma Gmbh 3-sulfonyl-3,7-diazabicyclo[3,3,1]nonane compounds and medicaments containing said compounds
US4912113A (en) * 1987-09-09 1990-03-27 Kali-Chemie Pharma Gmbh 3,7-diazabicyclo(3,3,1)nonane compounds and pharmaceutical compositions containing such compounds
US5164401A (en) * 1990-06-15 1992-11-17 Kali-Chemie Pharma Gmbh Method of diuretic treatment with 3,7-diazabicyclo[3,3,1]nonane compounds
US6291475B1 (en) 1997-12-17 2001-09-18 Astrazeneca Ab Bispidine antiarrhythmic compounds
US20040229900A1 (en) * 1999-06-16 2004-11-18 Astrazeneca Ab Bispidine compounds useful in the treatment of cardiac arrythmias
US6887881B1 (en) 1999-06-16 2005-05-03 Astrazeneca Ab Bispidine compounds useful in the treatment of cardiac arrythmias
US20050004113A1 (en) * 1999-06-16 2005-01-06 Astrazeneca Ab New bispidine compounds useful in the treatment of cardiac arrhythmias
US7038054B1 (en) * 1999-09-03 2006-05-02 Pharmacopeia Drug Discovery, Inc. Diazabicyclononane scaffold for combinatorial synthesis
US6559162B2 (en) 1999-12-23 2003-05-06 Astrazeneca Ab Azabicyclooctane derivatives useful in the treatment of cardiac arrhythmias
US20030212095A1 (en) * 2000-07-07 2003-11-13 Kjell Andersson New bispidine compounds and their use in the treatment of cardiac arrhythmias
US6808924B1 (en) 2000-07-11 2004-10-26 Claudia Lanari Mouse mammary tumor lines expressing estrogen and progesterone receptors
US20040039199A1 (en) * 2000-10-02 2004-02-26 Magnus Bjorsne Oxabispidine compound useful in the treatment of cardiac arrhythmias
US7012074B2 (en) 2000-10-20 2006-03-14 Astrazeneca Ab 3,8-Diazabicyclo[3.2.1]octanes and their use in the treatment of cardiac arrhythmias
US20040023971A1 (en) * 2000-10-20 2004-02-05 Magnus Bjorsne 3,8-Diazabicyclo[3.2.1]octanes and their use in the treatment of cardiac arrhythmias
US7144914B2 (en) 2001-02-02 2006-12-05 Astrazeneca Ab 3,7-diazabicyclo[3.3.0]octanes and their use in the treatment of cardiac arrhythmias
US20040053986A1 (en) * 2001-02-02 2004-03-18 Magnus Bjorsne 3,7-Diazabicyclo[3.3.0]octanes and their use in the treatment of cardiac arrhythmias
US7354917B2 (en) 2004-06-15 2008-04-08 Astrazeneca Ab Oxabispidine compounds and their use in the treatment of cardiac arrhythmias
US20070259864A1 (en) * 2004-06-15 2007-11-08 Astrazeneca Ab Novel Oxabispidine Compounds and Their Use in the Treatment of Cardiac Arrhythmias
WO2005123748A1 (en) 2004-06-15 2005-12-29 Astrazeneca Ab Novel oxabispidine compounds and their use in the treatment of cardiac arrhythmias
US20080146812A1 (en) * 2004-06-15 2008-06-19 Astrazeneca Ab Novel Oxabispidine Compounds And Their Use In The Treatment Of Cardiac Arrhythmias
US20080207899A1 (en) * 2004-06-15 2008-08-28 Astrazeneca Ab Novel Oxabispidine Compounds And Their Use In The Treatment Of Cardiac Arrhythmias
US20080249086A1 (en) * 2004-06-15 2008-10-09 Astrazeneca Ab Novel Oxabispidine Compounds And Their Use In The Treatment Of Cardiac Arrhythmias
US20080319198A2 (en) * 2004-06-15 2008-12-25 Astrazeneca Ab Novel Oxabispidine Compounds And Their Use In The Treatment Of Cardiac Arrhythmias
US20090099162A2 (en) * 2004-06-15 2009-04-16 Astrazeneca Ab Novel Oxabispidine Compounds And Their Use In The Treatment Of Cardiac Arrhythmias
US7648985B2 (en) 2004-06-15 2010-01-19 Astrazeneca Ab Oxabispidine compounds and their use in the treatment of cardiac arrhythmias
US20090054422A1 (en) * 2005-06-13 2009-02-26 Astrazeneca Ab New Oxabispidine Compounds For The Treatment Of Cardiac Arrhythmias
US7928225B2 (en) 2005-06-13 2011-04-19 Astrazeneca Ab Oxabispidine compounds for the treatment of cardiac arrhythmias

Also Published As

Publication number Publication date
ATA451475A (de) 1977-10-15
BE830153A (fr) 1975-12-12
SE420727B (sv) 1981-10-26
JPS5111791A (xx) 1976-01-30
FR2274300A1 (fr) 1976-01-09
DE2428792A1 (de) 1976-01-02
CA1058181A (en) 1979-07-10
SE7506743L (sv) 1975-12-15
GB1445967A (en) 1976-08-11
AT343660B (de) 1978-06-12
FI57759B (fi) 1980-06-30
FI57759C (fi) 1980-10-10
NL7506886A (nl) 1975-12-16
CH618168A5 (xx) 1980-07-15
FR2274300B1 (xx) 1978-11-10
FI751726A (xx) 1975-12-15

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